HIV evolution and diversity in ART-treated patients

Abstract

Characterizing HIV genetic diversity and evolution during antiretroviral therapy (ART) provides insights into the mechanisms that maintain the viral reservoir during ART. This review describes common methods used to obtain and analyze intra-patient HIV sequence data, the accumulation of diversity prior to ART and how it is affected by suppressive ART, the debate on viral replication and evolution in the presence of ART, HIV compartmentalization across various tissues, and mechanisms for the emergence of drug resistance. It also describes how CD4+ T cells that were likely infected with latent proviruses prior to initiating treatment can proliferate before and during ART, providing a renewable source of infected cells despite therapy. Some expanded cell clones carry intact and replication-competent proviruses with a small fraction of the clonal siblings being transcriptionally active and a source for residual viremia on ART. Such cells may also be the source for viral rebound after interrupting ART. The identical viral sequences observed for many years in both the plasma and infected cells of patients on long-term ART are likely due to the proliferation of infected cells both prior to and during treatment. Studies on HIV diversity may reveal targets that can be exploited in efforts to eradicate or control the infection without ART.

Keywords: Antiretroviral therapy (ART); Expanded clones; HIV diversity; HIV genetics; HIV persistence; HIV replication; HIV reservoir.

Fig. 1

Without ART, about 10⁶–10⁹ CD4+ T cells are infected daily by HIV-1 [141] (a). The HIV-1 population accumulates genetic diversity with each round of viral replication at a rate of about 1 mutation in 10⁵ nucleotides copied [142] (b). An unknown fraction of the infected CD4+ T cells persist despite infection and undergoes cellular proliferation [16, 17] (c). Some clonally expanded populations of HIV-1 infected cells carry proviruses that can generate virus particles [77] (d). It has been shown that the identical sequences observed in persistent viremia on ART can originate from expanded clones [77] (e)